We reported (Olkhanud et al, Vaccine, 2011) that, by modifying a vaccine formulation, we devised the Alzheimer's disease (AD) vaccine, termed Abeta-CoreS. The vaccine induces a potent humoral response and alleviates AD even if used at the onset of the disease, i.e. in old mice when traditional vaccines are ineffective. Thus, despite aging-associated B cell impairment, humoral responses to vaccines can be improved in the elderly. To understand this process, we are evaluating B cells in aging mammals. Recently we reported a new type of B cells, termed 4BL cells (Lee-Chang et al., Blood, 2014) that accumulate in aging humans, monkeys and mice and induce the generation of granzyme B (GrB) and perforin CD8+T cells. As such, the 4BL cells retard tumor growth in aging via inducing cytolytic antitumor CD8+T cells. Now, we report that we have elucidated (i) the origin of 4BL cells and (ii) the mechanism of their induction. We found that 4BL cells are derived from innate B1a cells that produce natural antibody. The implication of this finding is that, contrary to current assumption, we demonstrate that aging dysregulates innate B1a cells by converting them from immune suppressive cells into potent inducers of cytolytic CD8+T cells. We also found that the conversion is induced by aging myeloid cells, which are also dysregulated in elderly subjects. Overall, the project is progressing well as planned. Recently,we have submitted the results of this stage of the study for publication (Lee-Chang et al., 2015). Considering the importance of 4BL cells in aging and the fact that B1a cells are key producers of natural antibody against self-antigens, we next explored whether they are involved in pathogenesis of the Alzheimer's disease (AD), which mostly manifests in the elderly subjects. We are breeding B-cell deficient (B-cell KO) mice with 2xTg-AD mice and old age 3xTg-AD mice, which develop AD symptoms in young and old age, respectively. Our preliminary study indicates that the loss of B cells in 2xTg-AD mice is lethal, as they die by 2-3 month of age. In contrast, no lethality is detected in 3xTg-AD mice without mature B cells. Although B-cell KO 3xTg-AD mice are still young and did not yet develop the AD symptoms, they already exhibit skewed immune cell responses. Thus, this study, which will be completed in one year, is promising to open a new and interesting insight in the role of B cells in pathogenesis of AD.